The present invention relates to novel radiopharmaceutical compositions and matrices and the use thereof. More particularly, the present invention relates to novel radiopharmaceutical compositions and matrices for use in radiotherapy.
It has been predicted that one-third of all individuals in the United States may develop cancer. Cancer remains second only to cardiovascular disease as a cause of death in this country. More than 20% of Americans die from cancer, and this figure has been rising steadily as the population ages and deaths from heart disease decline. In the U.S., malignancy accounted for 526,000 deaths in 1992. Breast cancer is the most common form of malignancy in women (and is considered non-preventable), whereas prostate cancer is the most common form of malignancy in men in the U.S.
In 1995, there were approximately 230,000 newly diagnosed cases of prostate cancer and more than 44,000 deaths from prostate cancer in the U.S. alone. The disease is rare before age 50, and its incidence increases with age. The frequency of prostate cancer varies in different parts of the world. For example, the U.S. has 14 deaths per 100,000 men per year compared with 22 for Sweden and 2 for Japan. However, Japanese immigrants to the U.S. develop prostatic cancer at a rate similar to that of other men in this country. This suggests that an environmental factor may be the principal cause for population differences.
Despite these statistics, the appropriate treatment for cancer of the prostate remains controversial. Methods of treatment have included radiotherapy, such as external beam radiotherapy, and prostatectomy. Of these, radiotherapies were developed in an effort to avoid the undesirable side effects, including impotence and occasional incontinence, which are often associated with prostatectomy. Nevertheless, radiotherapies, and especially external beam therapies, may also produce undesirable side effects. Specifically, chronic complications after full courses of external beam radiation often occur, including impotence, chronic proctitis and rectal stricture, fistula or bleeding. In addition, it is not clear whether external beam radiation actually eradicates prostate cancer, because many patients in whom progression of the tumor is slowed or halted have persistent tumor on rebiopsy. The biologic potential of these persistent tumors is not clear. Also, once external beam radiation has been initiated, other methods of treatment, such as those involving surgery, are generally prohibited thereafter.
An alternative to external beam radiation treatment is brachytherapy. Brachytherapy generally refers to radiotherapy in which the source of radiation is located proximate the area of the body which is being treated. Brachytherapy typically involves the implantation of a radiation source, commonly referred to as xe2x80x9cseedsxe2x80x9d, directly into a tumor. These seeds may consist of radioisotopes or radiolabelled compounds. Brachytherapy offers the appealing concept of delivering a high dose of radiation to a confined area with relative sparing of adjacent normal tissue. Brachytherapy is one of the oldest techniques of radiotherapy for prostate cancer. In 1911, the first report on brachytherapy treatment for prostate cancer, which involved the insertion of radium into the prostatic urethra via catheter, was published. O. Pasteau et al., Rev. Malad. Nutr., pp. 363-367 (1911). Over the past 10 years, improvements in methods for brachytherapy have been stimulated by advances in technology, including innovative afterloading techniques, treatment planning by computer-based dosimetry analysis, and modem imaging modalities, as well as an improved understanding of the radiobiology associated with different dose rates of radiation. As a result, brachytherapy has been used successfully in the treatment of many cancers other than prostate cancer, including carcinomas of the cervix, breast, endometrium, head and neck.
The prostate is located adjacent to the critical structures of the bladder, urethra and rectum, and is therefore well-suited to confined radiation doses created by the implantation of radioactive seeds. Brachytherapy can deliver more radiation to the prostate with less dosages to the surrounding normal tissue than conventional external-beam radiation therapy. This higher intraprostatic dose should theoretically result in more effective tumor treatment, with fewer complications. However, the use of brachytherapy for carcinoma of the prostate is controversial because of the mixed results which have been reported and because of the availability of other treatment methods.
Methods of implantation in brachytherapy may involve temporary implantation, where the radiation source is left in the patient for a defined period of time and thereafter removed, or permanent implantation, where the radiation source is implanted permanently into the patient and is permitted to decay over a period of time into an inert state. Included among the radioisotopes which have been employed in brachytherapy include iodine 125 (125I), gold 198 (198Au), palladium 103 (103Pd), ytterbium 169 (169Yb) and iridium 192 (192Ir).
Radiation sources, such as radioisotopes, are characterized by the kind and energy of particles and/or photons which they emit, as well as their half-life. Radioisotopes, such as 192Ir and 198Au, which are typically encapsulated, for example, in titanium, generally deliver only photons to the patient which may penetrate further into tissue. The position of these sources is generally less critical to the achievement of a homogenous dose. However, this greater depth of radiation penetration may result in a greater exposure of surrounding normal tissue to radiation. The radiation of low to moderate energy sources, such as 125I, 103Pd and 169Yb, may deliver a more confined dose of radiation, but should be placed in vivo with great precision to avoid areas of underdosage (cold spots) in the cancer due to the limited penetration of the low-energy radiation, as well as the exposure to radiation of nearby healthy tissue, such as the urethra and rectum. Thus, the delivery of an effective dosage of radiation with radiation sources that are currently available can be difficult.
Phosphorous 32 (32P) has also been used in brachytherapy. For example, radiotherapy of cystic brain tumors with 32P is reported in V. Tassan et al., J. Nucl. Med., Vol. 26(11), pp. 1335-1338 (1985). 32P can be a desirable isotope for brachytherapy since it is a pure xcex2xe2x88x92 emitter. The radiation emitted from 32P has a maximum penetration in water of 7 to 8 mm and a mean penetration in water of 1 to 4 mm. D. Van Nostrand et al., Nuclear Medicine Annual, Raven Press, New York (1985). 32P is generally incorporated in radiopharmaceutical as the phosphate salt, particularly as chromic phosphate (Cr32PO4). See, e.g., J. T. Sprengelmeyer et al., The Journal of Nuclear Medicine, Vol. 31(12), pp. 2034-2036 (1990). However, such phosphate salts may be soluble in blood plasma and, accordingly, may be distributed throughout the body by the circulatory system. As a result, the phosphate salts may circulate from the site of implantation to other, non-cancerous regions of the body, including bone marrow and liver. L. J. Anghileri, International Journal of Applied Radiation and Isotopes, Vol. 16, pp.623-630 (1965). This is highly undesirable in that it may result in the exposure of normal tissues to potentially harmful radiation. In addition, this solubility in blood plasma may result in a reduction in the concentration of phosphate salt at the site of implantation and, accordingly, a reduction in the amount of radioactivity to which the tumor is exposed. This may result in inefficient or incomplete treatment and continued growth of the tumor.
Accordingly, new and/or better radiopharmaceuticals, as well as methods for the treatment of disease are needed. The present invention is directed to these, as well as other, important ends.
The present invention is directed, in part, to radiopharmaceuticals. Specifically, in one embodiment, there is provided a radiopharmaceutical composition which comprises a radioactive salt of the Formula I
Mz+HxP2O7xe2x80x83xe2x80x83(I)
wherein:
M is a metal ion;
x is an integer from 0 to 3; and
z is an integer from 1 to 4;
with the provisos that the sum of x and z is equal to 4, and at least one of M, H, P and O comprises a radioisotope; and a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a radiopharmaceutical composition comprising a radioactive salt of pyrophosphoric acid and a pharmaceutically acceptable carrier.
Yet another embodiment of the invention relates to a radioactive salt of pyrophosphoric acid.
Still another embodiment of the invention relates to a solid radiopharmaceutical matrix comprising a biocompatible sleeve which substantially surrounds a radiopharmaceutical composition comprising a radioactive salt of pyrophosphoric acid and one or more polymeric resins.
Another embodiment of the invention relates to a process for the preparation of a radiopharmaceutical composition. The process comprises providing a radioactive salt of pyrophosphoric acid, and combining the salt with a pharmaceutically acceptable carrier.
Still another embodiment of the invention relates to a process for the preparation of a solid radiopharmaceutical matrix. The process comprises providing a biocompatible sleeve which substantially surrounds a mixture of a radioactive salt of pyrophosphoric acid and a curable polymeric resin, and curing said resin.
Yet another embodiment of the invention relates to a radiopharmaceutical kit comprising a radioactive salt of pyrophosphoric acid.
Highly desirable and unexpected benefits are achieved with embodiments of the present invention. Specifically, the novel radioactive salts described herein, and compositions and matrices containing them, are highly useful in methods for the treatment of diseases, such as cancer, especially treatment methods involving brachytherapy. The radioactive salts and radiopharmaceutical compositions and matrices of the present invention are generally substantially insoluble in aqueous media, including blood and other bodily fluids. Accordingly, the present radioactive materials generally do not solubilize and circulate in the blood to a location in the body which is different from the site of implantation. Thus, the present invention may avoid the highly undesirable exposure of normal tissues in the body to potentially harmful radiation, which may occur, for example, with radiopharmaceuticals of the prior art. In addition, since the implanted radiopharmaceutical compositions and/or matrices substantially remain at the site of implantation, the cancer may be treated with desirable and controllable dosages of radiation.
These and other aspects of the invention will become more apparent from the present specification and claims.